These studies are designed to provide preclinical information for the development of medications to be used in the treatment of drug abuse. This work utilizes leads developed in studies of the basic mechanisms of the effects of cocaine in order to further develop pharmacological means for modulating behavioral and toxic actions of cocaine. New chemical entities (synthesized in-house and from outside sources) for safety and efficacy in the design of potential rational treatment strategies. The primary findings and implications for the current year and future directions are: (1) Buprenorphine protects against the lethal effects of cocaine. The mechanism by which this effect occurs appears to be mu-receptor mediated. The effect was stereospecific, and did not occur in a strain of mice that was mu-receptor deficient. Other mu agonists were equally efficacious with potencies that varied according to their relative affinities for the mu receptor. Drugs that competitively or non-competitively block the N-methyl-D-aspartate receptor were found to protect against the high-dose convulsant effects of cocaine. This protection was afforded at doses of cocaine that produced effects that could not be antagonized by standard anticonvulsants. These studies suggest a novel avenue for developing new treatments for seizures induced by cocaine overdose. Work on other modulators of this receptor and its associated mechanisms are in progress. Other studies are being conducted in order to develop a model for assessing cocaine withdrawal phenomena. A syndrome of hypersensitivity to dopaminergic stimulation after withdrawal from high doses of cocaine has been characterized. If this phenomenon proves to be a valid model of cocaine dependence it will be utilized for evaluating potential cocaine-withdrawal treatment agents.